Evasive action revealed

From left, Drs. Zhenpeng Dai, Thomas Spies, Veronika Groh and research technician Kimberly Smythe, focused on a tumor-produced protein called MIC. In early tumor development, MIC helps the body fight cancer cells. At later stages, massive amounts of MIC have the opposite effect.

Photo by Dean Forbes

Like cells infected with viruses or other disease-causing microbes, tumor cells send out signals that alert the immune system to the dangers of their presence. Yet the body's natural defenses often fail to provide adequate protection, as evidenced by the number of people who develop cancer.

A recent study from Dr. Thomas Spies' lab in the Clinical Research Division sheds new light on how tumors prevent their own demise. The scientists found that tumors can manipulate the immune system to stop it from attacking cancer cells, allowing them to multiply and spread.

The researchers found that as tumors grow, they produce massive amounts of a protein that causes normally helpful immune cells to block attempts by the immune system to attack the cancer. The discovery offers scientists a new way to think about boosting the body's natural ability to fight cancer.

"If one could prevent a tumor from releasing the protein, it could be beneficial in terms of helping sustain the immune system's normal capacity to mount an anti-tumor response," Spies said.

Dr. Veronika Groh led the study, which appears in the July issue of Nature Immunology. Co-authors include Kimberly Smythe and Dr. Zhenpeng Dai.

Tumors produce many types of abnormal proteins, which play different roles in tumor development. The new research focused on one of them, a protein long studied in the Spies Lab called MIC. In the early stages of cancer, MIC actually aids in the body's efforts to destroy cancer cells. At this time, MIC is produced at low levels by tumor cells and remains tethered to the surface of the cancerous cells. This moderate amount of MIC protein stimulates certain immune-system cells to mobilize other disease-fighting cells to attack and destroy the cancer.

At later stages of growth, tumor cells begin to produce massive amounts of MIC — so much that it is shed from tumor cells into the blood. The MIC overload now has an opposite effect, causing the once-helpful cells to signal the disease-fighters to self-destruct or stop growing.

Both the helpful and destructive effects of MIC are relayed through another protein that has been well studied in Spies' lab, called NKG2D. The NKG2D protein sits on the surface of certain immune cells. MIC and NKG2D fit together like a lock and key and trigger different responses. While moderate stimulation of NKG2D by MIC causes NKG2D to spur helpful immune responses, over-stimulation has the opposite effect.

The findings may have important implications for the development and refinement of cancer therapies that rely on harnessing the innate potential immune system — treatments collectively known as immunotherapy. A number of Center researchers are developing immunotherapy approaches for blood and solid-tumor cancers including leukemia, lymphoma, melanoma, and ovarian and breast tumors.

Groh noted that a recent study has found preliminary evidence that inactivating the MIC protein that is shed into the blood can overcome its ability to suppress the immune system. She said the lab is now trying to understand exactly how an abundance of MIC causes the once-helpful cells to suppress the immune response, which may provide additional insight into manipulating this response for the benefit of cancer therapy. The Avon Foundation Breast Cancer Immunotherapy Research Initiative and the National Institutes of Health funded the research.